The gene frequencies and haplotype frequencies for the alleles of the C4A and C4B loci were determined in a population of 39 unrelated Italian patients with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21-OH) deficiency and compared with the frequencies of the C4 alleles and C4 haplotypes present on the normal parental HLA haplotypes (i.e., the parental HLA haplotypes which did not carry the 21-OH deficiency allele). There was a decrease in the C4A*QO (null) allele among the patients (uncorrected P < 0.05) and a slight but statistically insignificant increase among the patients of the C4A*4 allele. The gene frequencies of the C4B locus were similar in the two groups. The very rare C4B*3 allele occurred in one patient. Overall, the C4A;C4B haplotypes were very similar in the two groups. In the patient group there was a slight increase in the frequency of the C4A*3; B*QO haplotype and the C4A*4; B*2 haplotype, whereas the C4A*QO; B*1 and C4A*QO; B*2 haplotypes were decreased or absent. One patient had the very rare haplotype C4A*QO;B*3, and was positive for the low frequency HLA-Bw47 determinant on the same haplotype. Seven patients with classical CAH and two patients with late onset 21-OH deficiency, who had the Bw47 antigen, were also found to have the unique complotype C4A*QO; B*3; BF*F: C2*C. Eleven additional patients with the HLA-B14, DR1-associated disease variant late onset 21-OH deficiency and four individuals with cryptic, asymptomatic 21-OH deficiency were also typed for the C4 electrophoretic variants. The 19 haplotypes with B14;DR1 all had the complotype C4A*2;B*2;BF*S;C2*C. The rare C2*B allele of the C2 locus was found on 10 haplotype with 21-OH deficiency. The complotype on eight of these was C4A*4;B*2;BF*S; C2*B. The C2*B was found only once on the normal parental HLA haplotypes. This study provides additional evidence for the hypothesis that the mutation on the 21-OH locus associated with HLA-Bw47 is unique and different from the mutation on the 21-OH locus resulting in the late onset or cryptic 21-OH deficiency allele associated with B14. It is likely that many independent mutations have acted on the 21-OH locus and that the clinical and biochemical heterogeneity of the 21-OH deficiency syndromes reflect heterogeneity in the DNA assaults.
ASJC Scopus subject areas
- Immunology and Allergy
- Pathology and Forensic Medicine